The ultimate goal of this SBIR proposal is to develop the novel pharmaceutical prodrug: DOX-PSASP-BBN- RGD as a molecular targeting chemotherapeutic agent for the treatment for prostate cancer. Prostate cancer is the most common cancer for men worldwide. Currently, early stage prostate cancer is treated with surgery, external beam radiation or radioactive seed implants. Hormonal therapy, chemotherapy and radiation are used for the treatment of advanced disease. However, no effective treatment is available for androgen independent (AI) prostate cancers. Conventional chemotherapy is often associated with substantial toxicity, which limits its use in prostate cancer treatment. Consequently, the therapy of late-stage prostate cancer remains a challenge, and new treatment approaches are needed. Therefore, to overcome those limitations in the treatment of prostate cancer, we developed a strategy intended to selectively kill prostate cancer cells using traditional cytotoxic chemotherapeutics. We hypothesize here that a targeted chemotherapeutic prodrug derived from a BBN-RGD heterodimer can selectively and effectively deliver the cytotoxic agent with a PSA Specific Peptide(PSASP) linker to prostate cancer cells, upon cleavage of the linker, the cytotoxic agent can then be released and kill the cancer cells specifically. Thus, the new prodrug is expected to have high targeting specificity for prostate cancer thus resulting in better efficacy and lower general toxicity compared with conventional chemotherapy. The first six month phase I of this proposal will focus on developing and synthesizing the prodrugs and in vitro characterization for their receptor binding affinity, hydrophilicity and cytotoxicity. The second phase of the proposal will focus on the pharmacokinetics and pharmacodynamics of DOX-PSASP- BBN-RGD prodrugs. We will carry out clinical monitoring systems using molecular imaging for treatment efficient study. We will obtain GMP quality DOX-PSASP-BBN-RGD conjugate. We will generate and compile sufficient data and reports for preclinical safety assessment of DOX-PSASP-BBN-RGD. The innovation in this proposal is developing a novel strategy which provides exciting promise to develop efficient targeted chemotherapy products that can be applied to various types of cancers.
Public Health Relevance: We will develop the novel prodrugs: DOX-PSASP-BBN-RGD for the targeted chemotherapy of prostate cancer. The new prodrugs have a highly potent cytotoxic agent, a heterodimer of two peptides specific for prostate cancer receptors and different cleavable linkers for targeted chemotherapy of prostate cancers. Because the prodrugs targets preferentially to specific receptors on cancer cells, we anticipated that the new prodrugs will have better efficacy and reduced peripheral toxicity. The same strategy should also be applicable to other cancer therapeutics.
Public Health Relevance Statement: We will develop the novel prodrugs: DOX-PSASP-BBN-RGD for the targeted chemotherapy of prostate cancer. The new prodrugs have a highly potent cytotoxic agent, a heterodimer of two peptides specific for prostate cancer receptors and different cleavable linkers for targeted chemotherapy of prostate cancers. Because the prodrugs targets preferentially to specific receptors on cancer cells, we anticipated that the new prodrugs will have better efficacy and reduced peripheral toxicity. The same strategy should also be applicable to other cancer therapeutics.
NIH Spending Category: Aging; Cancer; Prostate Cancer; Urologic Diseases
Project Terms: (8S-cis)-10-[(3-Amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroacetyl)-1-methoxy-5,12-naphthacenedione; 14-Hydroxydaunomycin; 5,12-Naphthacenedione, 10-((3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, (8S-cis)-; Adriamycine; Adverse effects; Affinity; Androgenic Agents; Androgenic Compounds; Androgens; Apoptosis; Apoptosis Pathway; Arg-Gly-Asp; Arginine-Glycine-Aspartic Acid Cell Adhesion Domain; Binding; Binding (Molecular Function); Biodistribution; Blood Serum; Bombesin Receptor; Bystander Effect; Cancer Model; Cancer Treatment; Cancer of Prostate; CancerModel; Cancers; Cell Death; Cell Death, Programmed; Cell surface; Cells; Chemotherapy Protocol; Chemotherapy Regimen; Chemotherapy, Cancer, General; Chemotherapy-Oncologic Procedure; Cleaved cell; Clinical; Clinical Protocols; Clinical Trials, Phase I; Clinical Trials, Phase II; Combination Chemotherapy Regimen; Coupling; Cytotoxic agent; Cytotoxic drug; DOX; Data Reporting; Definitive Radiation Therapy; Detection; Diagnosis; Disease; Disorder; Dose-Limiting; Doxorubicin; Doxorubicina; Drug Delivery; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Drug Precursors; Drug Targeting; Drug Targetings; Drugs; EBRT; EC 3.4.21.34; Early-Stage Clinical Trials; Endocrine Therapy; Endothelial Cells; Enzymes; Evaluation; External Beam RT; External Beam Radiation Therapy; External Radiation; Extracellular Matrix, Integrins; F element; Figs; Figs - dietary; Fletcher Factor; Fluorine; Formulation; Formulations, Drug; Goals; Hormonal Therapy; Hydrolysis; Hydroxyl Daunorubicin; Hydroxyldaunorubicin; Image; Imaging Procedures; Imaging Techniques; In Vitro; Industry; Integrins; KLK3; Kallikrein 3; Killings; Kinetic; Kinetics; Label; Lead; Libraries; Lytotoxicity; Malignant Cell; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; Malignant Neoplasms; Malignant Tumor; Malignant Tumor of the Prostate; Malignant neoplasm of prostate; Malignant prostatic tumor; Mammals, Mice; Maximal Tolerated Dose; Maximally Tolerated Dose; Maximum Tolerated Dose; Medical Imaging, Positron Emission Tomography; Medication; Metastasis; Metastasize; Metastatic Neoplasm; Metastatic Tumor; Methods; Mice; Molecular Interaction; Molecular Target; Monitor; Murine; Mus; NMBR; Neoplasm Metastasis; Operation; Operative Procedures; Operative Surgical Procedures; P-30 Antigen; PET; PET Scan; PET imaging; PETSCAN; PETT; Parents; Patients; Pb element; Peptides; Peripheral; Pharmaceutic Preparations; Pharmaceutical Agent; Pharmaceutical Preparations; Pharmaceuticals; Pharmaceutics; Pharmacodynamics; Pharmacokinetics; Pharmacologic Substance; Pharmacological Substance; Pharmacy (field); Phase; Phase 1 Clinical Trials; Phase 2 Clinical Trials; Phase I Clinical Trials; Phase I Study; Phase II Clinical Trials; Plasma Kallikrein Precursor; Plasma Prekallikrein; Positron Emission Tomography Scan; Positron-Emission Tomography; Pro-Drugs; Prodrugs; Production; Programs (PT); Programs [Publication Type]; Prostate CA; Prostate Cancer; Prostate Specific Antigen Preproprotein; Prostate-Specific Antigen; Prostatic Cancer; Proteins; Proton Magnetic Resonance Spectroscopic Imaging; Quimioterapia; RGD; RGD (peptide); RGD (sequence); RGD Cell Adhesion Domain; RGD Domain; RGD Motif; RGD Tripeptide Sequence; RGD tripeptide; Rad.-PET; Radiation; Radioactive; Receptor Protein; Receptors, Gastrin-Releasing Peptide; Receptors, Neuromedin B; Recurrence; Recurrent; SBIR; SBIRS (R43/44); Secondary Neoplasm; Secondary Tumor; Secondary to; Seed Implant; Seed Implantation; Semenogelase; Seminin; Serum; Small Business Innovation Research; Small Business Innovation Research Grant; Specificity; Staging; Stromal Cells; Structure; Surgical; Surgical Interventions; Surgical Procedure; Survival Rate; System; System, LOINC Axis 4; Technics, Imaging; Testing; Therapeutic; Therapeutic Androgen; Toxic effect; Toxicities; Treatment Efficacy; Treatment Side Effects; Tumor Cell; Tumor Cell Migration; Xenograft Model; advanced disease; androgen independent prostate cancer; anticancer therapy; arginyl-glycyl-aspartic acid; base; cancer cell; cancer chemotherapy; cancer metastasis; cancer therapy; cancer type; chemotherapeutic agent; chemotherapy; cleaved; cytotoxic; cytotoxicity; density; design; designing; disease/disorder; drug/agent; effective therapy; experience; experiment; experimental research; experimental study; external-beam radiation; gamma-Seminoprotein; gene product; hK3 Kallikrein; heavy metal Pb; heavy metal lead; hormone therapy; hydrophilicity; imaging; immunopathology; in vivo; innovate; innovation; innovative; kininogenin; malignancy; men; men's; molecular imaging; multimodality; necrocytosis; neoplasm/cancer; neoplastic cell; new approaches; novel; novel approaches; novel strategies; novel strategy; phase 1 study; phase 1 trial; phase 2 study; phase 2 trial; phase I trial; phase II trial; preclinical safety; programs; protocol, phase I; protocol, phase II; public health relevance; ray (radiation); receptor; receptor binding; research study; response; side effect; study, phase II; surgery; therapeutic efficacy; therapeutic target; therapeutically effective; therapy adverse effect; treatment adverse effect; treatment effect; treatment strategy; tumor; uptake
